Insulin is a hormone that plays a major role in the regulation of glucose metabolism by stimulating the uptake of glucose in liver, muscle, and fat tissue. Glucose is stored in such tissue and metabolized for energy. Failure to produce insulin, dysregulation of insulin, or resistance to insulin lead to metabolic diseases and disorders, for example, diabetes.
Glucose-dependent insulinotropic polypeptide (GIP) is a 42-residue peptide that is secreted by the upper gut. Both carbohydrates and lipids stimulate the secretion of GIP. Along with GLP-1, GIP is an incretin, meaning that it has the ability to stimulate the release of insulin. The effects of GIP are mediated by its binding to GIP receptor (GIPR). It is believed that this binding stimulates cAMP which facilitates glucose stimulated insulin release in the pancreatic β-cells.
In vivo, native GIP is rapidly degraded by the enzyme dipeptidyl peptidase IV (DPPIV) which removes the two N-terminal residues, Tyr-Ala. The half life of native GIP in vivo is about 2 to 7 minutes depending on species. The metabolite (GIP 3-42) does not activate GIPR and, in fact, serves as an antagonist of GIPR. In addition, the metabolite is readily cleared in humans. As such, the effectiveness of native GIP as a therapeutic is limited.
The present invention relates to the development of truncated GIP (1-42) analogs which retain the potency of GIP and its ability to bind GIPR, serving as an agonist thereof, while having improved plasma stability and increased half life in vivo as compared with native GIP.